title: IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.
abstract: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.
authors.affiliation: Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA. orange@upenn.edu
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Sumita
authors.initials: S
authors.lastname: Roy-Ghanta
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.forename: Saumya
authors.initials: S
authors.lastname: Maru
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Rak
authors.forename: Keri B
authors.initials: KB
authors.lastname: Sanborn
authors.forename: Anders
authors.initials: A
authors.lastname: Fasth
authors.forename: Rushani
authors.initials: R
authors.lastname: Saltzman
authors.forename: Allison
authors.initials: A
authors.lastname: Paisley
authors.forename: Linda
authors.initials: L
authors.lastname: Monaco-Shawver
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.forename: Rahul
authors.initials: R
authors.lastname: Pandey
mesh_terms: D000199:Actins / Q000378:metabolism*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000199:Actins; C508594:IL2 protein, human; D007376:Interleukin-2; C495767:WAS protein, human; C120152:WASF2 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D051300:Wiskott-Aldrich Syndrome Protein Family